2. Cholesterol Metabolism By Amr S. Moustafa, M.D.; Ph.D.

3. Outlines  Overview and Functions  Liver cholesterol pool  Structure and Types  Synthesis and Regulation  Bile acids and salts  Enterohepatic circulation

4. Overview and Functions  Major Sterol of animal tissues  Component of cell membranes  Precursor for: Bile acids & salts Vitamin D Steroid hormones: Mineralocorticoids e.g., Aldosterone Glucocorticoids, e.g., Cortisol Sex hormones, e.g., Testosterone Estrogen & progesterone  Hypercholesterolemia: Atherosclerosis & CAD

5. Liver Cholesterol Pool

6. Cholesterol: Structure

7. Cholesterol: Types Animal sterol: Cholesterol Plant sterol: β-Sitosterol  Poor intestinal absorption  Active transport to intestinal lumen  Block cholesterol absorption  Dietary treatment of hypercholesterolemia (Trans fatty acid-free margarine) Animal and plant sterols:

8. Cholesterol: Types Free cholesterolEsterified cholesterol OH at C3 Hydrophobic Membranes Cells Plasma Transport Bile Free Less Found Variable Less LDL/HDL Present (PL & bile salts) Fatty acid More Absent Low levels Most HDL/LDL Absent CONT’D

9. Cholesterol: Synthesis  All tissues, e.g., Liver, Intestine, Adrenal cortex, & Reproductive organs  Cytosol & ER  Building blocks: Acetyl CoA  Reducing equivalents: NADPH  Thioester bond &ATP  Rate-limiting enzyme: HMG CoA reductase

10. CONT’D Cholesterol: Synthesis CONT’D

11. Cholesterol: Synthesis CONT’D Internsic ER membrane Catalytic domain, cytosol

13. Regulation of Cholesterol Synthesis Sterol-dependent: Cholesterol content SREBP Stability of mRNA & HMG CoA protein Hormonal-dependent: Insulin (+), Glucagon (-) (A) HMG CoA gene expression: (B) Phosphorylation/dephosphorylation: Sterol-independent, Hormonal-dependent Dephospho-form: Active (C) Statin drugs: Reversible, competitive inhibitors

14. Regulation of Cholesterol Synthesis CONT’D

15. Cholesterol: Degradation  Cholesterol secretion into bile: Cholesterol Coprostanol Choleastanol Reduced products Bacteria Neutral fecal sterols Intact sterol nucleus:  Bile acids & salts

16. Bile Acids and Salts Primary bile acids: Cholic acid and Chenodeoxycholic acid Bile acids: 24 C, 2 or 3 OH -COOH at side chain Amphipathic, Emulsifying agents Bile salts (Conjugated bile acids): amide-linked with glycine or taurine Glycocholic Taurocholic Glycochenodeoxycholic Taurochenodeoxycholic

18. Bile Acids: Synthesis

19. Bile Salts  More effective detergent  -COOH (glycine) & -SO 4 (taurine): Fully-ionized  Only bile salts, but not acids, found in bile  Important for cholesterol excretion: metabolic products Solubilizer for cholesterol in bile  Genetic deficiency: Exogenous bile acids

21. Secondary Bile Acids Bile salts Glyco- or Tauro-cholic -Chenodeoxycholic Bile acids Cholic acid Chenodeoxycholic 2° Bile acids Deoxycholic acid Lithocholic Intestinal bacteria Glycine Taurine OH

22. Enterohepatic Circulation

23. Cholelithiasis Causes: bile salts in bile: malabsorption syndrome Biliary tract obstruction hepatic dysfunction Biliary cholesterol excretion Treatment:  Bile acid replacement therapy  Surgical

24. Hypercholesterolemia Cholesterol blood level: Familial Hypothyroidism Diabetes mellitus Nephrotic syndrome Obstructive jaundice Treatment:  Dietetic  Bile acid sequestrants, e.g., Cholestyramine  Statin drugs